The voltage-gated Na+ channel plays an important role in many serious arrhythmias and is the target of many antiarrhythmic drugs. While these drugs may control arrhythmia, they are often proarrhythmic and may contribute to sudden cardiac death. Their clinical efficacy and proarrhythmic potential can be attributed to their kinetic interaction with the Na+ channel. Major factors controlling their pharmacokinetics relate to the differential affinities toward gating states of the Na+ channel and differential uses of access paths to their binding site, guarded by activation and inactivation gates. These factors also underlie the differences in clinical behavior of open-channel blocking drugs such as flecainide and quinidine and inactivated-channel blocking drugs such as lidocaine and mexilitine. The current proposal addresses issues of drug- access paths in three parts; 1) to determine whether lidocaine uses an external hydrophilic path to affect its pharmacokinetics, 2) to develop methods to define hydrophilic and hydrophobic access paths important in the pharmacokinetics, and 3) to investigate possible differences in the access paths used by open-channel and inactivated-channel blocking drugs. The study may also result in further information on structural features of the Na+ channel important in drug-channel interaction and offer better insights for safer use and new design of antiarrhythmic drugs.